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- Title
Inconsistent hepatic antifibrotic effects with the iron chelator deferasirox.
- Authors
Sobbe, Amy; Bridle, Kim R; Jaskowski, Lesley; Guzman, C Erika; Santrampurwala, Nishreen; Clouston, Andrew D; Campbell, Catherine M; Subramaniam, V Nathan; Crawford, Darrell H G
- Abstract
Background and Aim Development of effective antifibrotic treatments that can be translated to clinical practice is an important challenge in contemporary hepatology. A recent report on β-thalassemia patients demonstrated that deferasirox treatment reversed or stabilized liver fibrosis independent of its iron-chelating properties. In this study, we investigated deferasirox in cell and animal models to better understand its potential antifibrotic effects. Methods The LX-2 stellate cell line was treated with 5 μ M or 50 μ M deferasirox (Exjade, Novartis Pharmaceuticals Australia, North Ryde, NSW, Australia) for up to 120 h. Three-week-old multidrug resistance 2 null ( Mdr2-/-) mice received oral deferasirox or vehicle for 4 weeks (30 mg/kg/day). Cells and liver tissue were collected for assessment of fibrosis and fibrogenic gene expression. Results In LX-2 cells treated with 50 μ M deferasirox for 12 h, α1( I)procollagen expression was decreased by 25%, with maximal reductions (10-fold) seen following 24-120 h of treatment. Similarly, α-smooth muscle actin ( αSMA) expression was significantly lower. Alterations in matrix remodeling genes, specifically decreased expression of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2, were observed. There was no significant difference in hepatic hydroxyproline content in Mdr2-/- mice following deferasirox administration (vehicle: 395 ± 27 μg/g vs deferasirox: 421 ± 33 μg/g). Similarly, no changes in the expression of fibrogenic genes were observed. Conclusion Despite reductions in α1( I)procollagen and αSMA expression and alterations in matrix degradation genes in LX-2 cells, deferasirox did not exhibit antifibrotic activity in Mdr2-/- mice. Given the positive outcomes seen in human trials, it may be appropriate to study deferasirox in other animal models of fibrosis and/or for a longer duration of therapy.
- Subjects
DEFERASIROX; IRON chelates; HEPATOLOGY; CELL lines; FIBROSIS
- Publication
Journal of Gastroenterology & Hepatology, 2015, Vol 30, Issue 3, p638
- ISSN
0815-9319
- Publication type
Article
- DOI
10.1111/jgh.12720